Refractory and Super-Refractory Status Epilepticus—an Update

Status epilepticus is a medical emergency with a high mortality. Early recognition and initiation of treatment leads to a better response and may improve outcomes. Refractory status epilepticus is defined as recurrent seizure activity despite two appropriately selected and dosed antiepileptic drugs including a benzodiazepine. The term “super-refractory status epilepticus” was introduced during the London–Innsbruck Colloquium on status epilepticus in 2011 and refers to status epilepticus that continues or recurs 24 h or more after the initiation of treatment with anesthetic antiepileptic drugs. This includes cases in which seizure control is attained after induction of anesthesia but recurs on weaning the patient off the anesthetic agent. This article reviews the approach to refractory status epilepticus and super-refractory status epilepticus, including management as well as common pathophysiological causes of these entities.     

Can anesthetic treatment worsen outcome in status epilepticus?

Status epilepticus refractory to first-line and second-line antiepileptic treatments challenges neurologists and intensivists as mortality increases with treatment refractoriness and seizure duration. International guidelines advocate anesthetic drugs, such as continuously administered high-dose midazolam, propofol, and barbiturates, for the induction of therapeutic coma in patients with treatment-refractory status epilepticus. The seizure-suppressing effect of anesthetic drugs is believed to be so strong that some experts recommend using them after benzodiazepines have failed. Although the rationale for the use of anesthetic drugs in patients with treatment-refractory status epilepticus seems clear, the recommendation of their use in treating status epilepticus is based on expert opinions rather than on strong evidence. Randomized trials in this context are lacking, and recent studies provide disturbing results, as the administration of anesthetics was associated with poor outcome independent of possible confounders. This calls for caution in the straightforward use of anesthetics in treating status epilepticus. However, there are still more questions than answers, and current evidence for the adverse effects of anesthetic drugs in patients with status epilepticus remains too limited to advocate a change of treatment algorithms.In this overview, the rationale and the conflicting clinical implications of anesthetic drugs in patients with treatment-refractory status epilepticus are discussed, and remaining questions are elaborated.This article is part of a Special Issue entitled “Status Epilepticus”.     

Neuron Specific Enolase,S100-beta protein and progranulin as diagnostic biomarkers of status epilepticus

Journal of Neurology - Status epilepticus (SE) is a life-threatening prolonged epileptic seizure. A rapid diagnosis is fundamental to initiate antiepileptic treatment and to prevent the development...     

IV levetiracetam in the management of non-convulsive status epilepticus

Introduction  

Status epilepticus (SE) is a medical emergency requiring prompt treatment to try to limit mortality and improve outcome. So far, newer antiepileptic drugs (AED) have not assumed a noticeable role in the treatment of SE. This may be in part due to the lack of IV forms for the newer AEDs. The IV form of Levetiracetam (IV-LEV) has recently become available and has a potential role in the treatment of SE.     

Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus

Status epilepticus (SE) is a neurological emergency, with high mortality and high morbidity among survivors, and novel therapeutic agents are needed to improve this picture. We examined the effects of the antiepileptic drug levetiracetam (LEV) in an experimental model of self-sustaining status epilepticus (SSSE), induced in rats by electrical stimulation of the perforant path. LEV's unique spectrum of anticonvulsant activity, very high therapeutic index, and neuroprotective properties, make it a potentially interesting agent in the treatment of SE. Pretreatment with LEV intravenously reduced (30 mg/kg) or prevented (50-1000 mg/kg) the development of self-sustaining seizures. Treatment during the maintenance phase of SSSE diminished (at 200 mg/kg) or aborted seizures (in doses of 500 or 1000 mg/kg). Addition of LEV significantly enhanced the anticonvulsant effects of diazepam (DZP), even when both drugs where given in doses far below their therapeutic level. We conclude that LEV deserves further evaluation in the treatment of status epilepticus.     

Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus

Status epilepticus is usually initially treated with a benzodiazepine such as diazepam. During prolonged seizures, however, patients often lose their sensitivity to benzodiazepines, thus developing pharmacoresistant seizures. In rats, administration of LiCl followed 20–24 h later by pilocarpine induces a continuous, self-sustained, and reproducible form of status epilepticus that can be terminated with diazepam when it is administered soon after the pilocarpine injection. However, when administered after a 45 min delay, diazepam is less effective. Previous findings have suggested that the development of pharmacoresistance is related to the stage of status epilepticus. In the present study, we characterized the seizure stage-dependence of diazepam pharmacoresistance. Following administration of different doses of diazepam at varying time intervals after specific behaviorally- and electrographically-defined seizure stages, stage-, time-, and dose-dependent pharmacoresistance to diazepam developed. We also studied two other antiepileptic drugs commonly used in the treatment of status epilepticus, phenobarbital and phenytoin. Consistent with previous studies, our results indicated a similar relationship between stage, time and dose for phenobarbital, but not for phenytoin. Our data are consistent with rapid modulation of GABA_A receptors during status epilepticus that may result in pharmacoresistance to antiepileptic drugs that enhance GABA_A receptor-mediated inhibition.     

Clinical features of convulsive status epilepticus: a study of 220 cases in western China

Background and purpose:  Convulsive status epilepticus (CSE) is the most common and life-threatening form of status epilepticus (SE). The aim of this study was to describe the clinical features of CSE in western China.
Methods:  Convulsive status epilepticus patients hospitalized from January 1996 to October 2007 were prospectively observed. Logistic regression was used to identify predictors of prognosis.
Results:  The average age of CSE patients ( n  = 220) was 37.5 years (SD 20.31), 50% of the patients had a history of epilepsy. The primary cause of CSE was central nervous system infection (32.7%), followed by discontinuation or reduction of antiepileptic drugs (AEDs; 15.5%). The median duration of CSE was 5 h and median duration of seizures before treatment was 2 h; both were longer in rural patients than in urban patients ( P  < 0.05). The fatality rate on discharge was 15.9%. Logistic regression analysis showed the duration of CSE [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03–1.07], a history of epilepsy (OR 0.35, 95% CI 0.14–0.89), and respiratory depression (OR 5.96, 95% CI 2.49–14.24) were independent predictors of CSE prognosis.
Discussion:  Central nervous system infection and AEDs withdrawal in epilepsy patients were the most important causes of CSE. There is a large gap between antiepileptic therapy in China and European Status Epilepticus guidelines.     

The treatment of status epilepticus

Status epilepticus (SE) is a life-threatening emergency that requires prompt treatment, including basic neuroresuscitation principles (the ABCs), antiepileptic drugs to stop the seizure, and identification of etiology. Symptomatic SE is more common in younger children. Treating the precipitating cause may prevent ongoing neurologic injury and facilitates seizure control. A systematic treatment regimen, planned in advance, is needed, including one for refractory status epilepticus (RSE). Here we emphasize definitions, clinical and electroencephalography stages, early treatment, special circumstances that may require immediate seizure control, and treatment of RSE. Because much clinical research in SE has been done in adults, we indicate the patient population studied.     

Bursts of high-frequency repetitive transcranial magnetic stimulation (rTMS), together with lorazepam,suppress seizures in a rat kainate status epilepticus model

BackgroundStatus epilepticus (SE) is a condition of prolonged or recurrent and often drug-resistant seizures where nonsedating SE therapy remains an important unmet need. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a means to suppress seizures but has not been extensively studied in models.ObjectivesWe aimed to test the antiepileptic potential of high-frequency rTMS in SE. As a step toward eventual coupling of rTMS with antiepileptic pharmacotherapy, we also tested whether high-frequency rTMS in combination with a low (ineffective but less likely to cause a side effect) lorazepam dose is as effective as a full lorazepam dose in suppressing seizures in a rat SE model.MethodsEEG was recorded to measure epileptic spike frequency in the rat kainate SE model. Epileptic spikes were counted before, during, and after either high-frequency rTMS treatment alone or high-frequency rTMS treatment in combination with lorazepam, a firstline SE treatment.ResultsWe found that rTMS alone decreases epileptic spike frequency only acutely. However, combinatory treatment with half-dose lorazepam together with rTMS was as effective as a full lorazepam dose.ConclusionWe report that high-frequency rTMS has modest antiepileptic potential alone but acts in complement with lorazepam to suppress seizures.     

Epilepsy in Wolf-Hirschhorn syndrome (4p-)

PURPOSE: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf-Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus. METHODS: We reviewed 11 cases of Wolf-Hirschhorn syndrome (age range, 2-25 years; SD, 7.2 years) and who were treated in Osaka University or Osaka Medical Center of Research Institute for Maternal and Child Health. RESULTS: In all patients, febrile or afebrile convulsions had developed. Epileptic seizures included alternative hemiconvulsions, generalized tonic-clonic seizures, focal clonic seizures, tonic seizures, and epileptic spasms. Seizures were often induced by a high fever or a hot bath. Status epilepticus occurred in all patients, including one patient who died at the first status epilepticus. In some cases, intratracheal intubation was needed because of respiratory insufficiency. The effective antiepileptic drugs for long-term use were sodium bromide (four of four), followed by clorazepate (CLP; one of two), and nitrazepam (NZP; two of four). Sodium bromide was particularly effective for preventing status epilepticus. The mean age of last status epilepticus in patients receiving sodium bromide (1 year 8 months) was significantly younger than that in those not treated with sodium bromide (3 year 4 months). CONCLUSIONS: We identified that, in most patients of Wolf-Hirschhorn syndrome, the frequency of both seizures and status epilepticus decreased gradually after age 5 years. However, during infancy, status epilepticus sometimes resulted in permanent disability or even death. We propose that sodium bromide should be used as the initial treatment for the prevention of the development of status epilepticus associated with Wolf-Hirschhorn syndrome.     

Stimulus-sensitive burst-spiking in burst-suppression in children: implications for management of refractory status epilepticus.

Status epilepticus refractory to sequential trials of multiple medication is a rare but significant problem in children. We describe stimulus sensitivity arising during the treatment of convulsive status epilepticus in children (stimulus-sensitive burst-spiking in burst-suppression). We reviewed retrospectively clinical and EEG features in six children (three months to ten years), with status epilepticus requiring intensive care, in whom tactile, auditory and visual stimulation induced myoclonic jerks and bursts of EEG spikes. Sensitivity was not present at onset, but appeared after 24 hours as myoclonic jerks of the eyes, face and limbs, irrespective of the modality and site of stimulation. These were associated with burst-suppression in the EEG, the induced spiking forming the burst component. Various antiepileptic drugs, including GABAergic and NMDA blockers had no effect, but halogenated agents (used in two patients) abolished the sensitivity. Two children died, but the remainder returned to their previous clinical state. We conclude that stimulus sensitivity may appear in the context of refractory status epilepticus treated with high-dose barbiturates. Outcome may be more favorable than previously reported in adults, mostly in the context of post-anoxic or toxic coma. Evaluation of ventilated children in status epilepticus should include electroclinical assessment using sensory stimulation. If present, the drug regime should be reviewed and halogenated agents considered.     

Refractory status epilepticus: A prospective observational study

Purpose: Status epilepticus (SE) that is resistant to two antiepileptic compounds is defined as refractory status epilepticus (RSE). In the few available retrospective studies, estimated RSE frequency is between 31% and 43% of patients presenting an SE episode; almost all seem to require a coma induction for treatment. We prospectively assessed RSE frequency, clinical predictors, and outcome in a tertiary clinical setting. Methods: Over 2 years we collected 128 consecutives SE episodes (118 patients) in adults. Clinical data and their relationship to outcome (mortality and return to baseline clinical conditions) were analyzed. Results: Twenty‐nine of 128 SE episodes (22.6%) were refractory to first‐ and second‐line antiepileptic treatments. Severity of consciousness impairment and de novo episodes were independent predictors of RSE. RSE showed a worse outcome than non‐RSE (39% vs. 11% for mortality; 21% vs. 63% for return to baseline clinical conditions). Only 12 patients with RSE (41%) required coma induction for treatment. Discussion: This prospective study identifies clinical factors predicting the onset of SE refractoriness. RSE appears to be less frequent than previously reported in retrospective studies; furthermore, most RSE episodes were treated outside the intensive care unit (ICU). Nonetheless, we confirm that RSE is characterized by high mortality and morbidity.     

Why we prefer levetiracetam over phenytoin for treatment of status epilepticus

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine‐resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time‐consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine‐resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment.     

Status epilepticus as a manifestation of hepatic encephalopathy

OBJECTIVES: Seizures have been described as a rare manifestation of hepatic encephalopathy. MATERIAL AND METHODS: We present a 54-year-old female, with 6-year history of decompensated, hepatitis B liver cirrhosis, admitted with generalized seizures. She reported a history of recurrent episodes of hepatic encephalopathy, spontaneous bacterial peritonitis, tense ascites and variceal hemorrhage. Neurologic examination revealed a comatose patient, without papilledema. Laboratory examinations were suitable with cirrhosis and mild renal failure. Blood gas examination revealed severe metabolic acidosis and hypoxemia. Plasma NH3+ levels upon admission were twice normal. Brain computed tomography and magnetic resonance imaging were normal. Electroencephalogram showed diffuse sharp waves, consistent with hepatic encephalopathy, grades III-IV. RESULTS: Status epilepticus was refractory to continuous antiepileptic treatment. However, it was resolved after 24-h therapy with lactulose. Blood NH3 levels were simultaneously normalized with clinical improvement. CONCLUSIONS: We consider the status epilepticus of our patient to be a rare manifestation of hepatic encephalopathy.     

New experimental therapies for status epilepticus in preclinical development

Starting with the established antiepileptic drug, valproic acid, we have taken a novel approach to develop new antiseizure drugs that may be effective in status epilepticus. We first identified that valproic acid has a potent effect on a biochemical pathway, the phosphoinositide pathway, in Dictyostelium discoideum, and we demonstrated that this may relate to its mechanism of action against seizures in mammalian systems. Through screening in this pathway, we have identified a large array of fatty acids and fatty acid derivatives with antiseizure potential. These were then evaluated in an in vitro mammalian system. One compound that we identified through this process is a major constituent of the ketogenic diet, strongly arguing that it may be the fatty acids that are mediating the antiseizure effect of this diet. We further tested two of the more potent compounds in an in vivo model of status epilepticus and demonstrated that they were more effective than valproic acid in treating the status epilepticus.This article is part of a Special Issue entitled “Status Epilepticus”.     

Mitochondrial diseases and status epilepticus

This narrative review focuses on the pathophysiology, diagnosis, and management of status epilepticus in the context of primary mitochondrial disease. Epilepsy is common in mitochondrial disease, reported in >20% of adult cases and 40%‐60% of pediatric cohorts. Status epilepticus is less frequently reported and appears to be associated with particular subgroups of mitochondrial disorders, namely defects of the mitochondrial DNA and its maintenance, and disorders of mitochondrial translation and dynamics. Mechanisms underlying mitochondrial status epilepticus are incompletely understood, and may include bioenergetic failure, oxidative stress, immune dysfunction, and impaired mitochondrial dynamics. Treatments tried in mitochondrial status epilepticus include antiepileptic drugs, anesthetic agents, magnesium, high‐dose steroids, immune globulins, vagus nerve stimulation, and surgical procedures, all with variable success. The outcome of mitochondrial status epilepticus is extremely poor, and effective therapeutic options have not been reported. Improved understanding of the mechanisms underpinning mitochondrial status epilepticus is needed in order to develop more effective treatments.     

Outcome prediction in patients with acute repetitive seizures: Application of the Status Epilepticus Severity Score

Acute repetitive seizures (ARS) pose a risk of hospital admission with status epilepticus and a mortality threat, which underscores the need for the early prediction of a clinical course. Unfortunately, little attention has been given to ARS in this context, even though we possess the appropriate predictive tools for the stages of status epilepticus. Therefore, the main aim of this study was to assess the prognostic value of the Status Epilepticus Severity Score (STESS) in the population of patients with ARS. The study included a population of 200 patients. Almost half of the patients had achieved seizure cessations after diazepam administration, whereas 19.5% progressed to status epilepticus despite antiepileptic drug treatment. Mortality reached 10.5% of the total population. The receiver operating characteristic (ROC) curve for prediction of death by the STESS had an area under the curve (AUC) of 0.901, with an optimal cutoff point for discrimination ≥2 (sensitivity 0.95, specificity 0.71, and Youden index 0.66). Hosmer‐Lemeshow indicated good calibration of the STESS (chi‐square goodness‐of‐fit test = 3.24; P = .919). The study shows excellent effectiveness of the STESS in the prognosis of the clinical course in patients with ARS. STESS may be a valuable tool for the proper planning of diagnostic and therapeutic activities in this population.     

Electrographic status epilepticus in children with critical illness: Epidemiology and outcome

Electrographic seizures and electrographic status epilepticus are common in children with critical illness with acute encephalopathy, leading to increasing use of continuous EEG monitoring. Many children with electrographic status epilepticus have no associated clinical signs, so EEG monitoring is required for seizure identification. Further, there is increasing evidence that high seizure burdens, often classified as electrographic status epilepticus, are associated with worse outcomes. This review discusses the incidence of electrographic status epilepticus, risk factors for electrographic status epilepticus, and associations between electrographic status epilepticus and outcomes, and it summarizes recent guidelines and consensus statements addressing EEG monitoring in children with critical illness.This article is part of a Special Issue entitled “Status Epilepticus”.     

Status epilepticus associated with pregnancy: A cohort study

BackgroundStatus epilepticus (SE) is a neurological emergency associated with a high mortality rate and long-term cognitive sequelae. Status epilepticus in pregnancy poses a tremendous threat to both mother and fetus, making a correct diagnosis and treatment a challenging task for clinicians. The prevalence, underlying etiology, and outcomes of pregnancy-related SE remain largely unknown.MethodsWe retrospectively studied all SE episodes (n = 366) in patients admitted to our neurological ICU over a period of 8.5 years. The patients who developed SE during pregnancy and within 6 months after delivery were considered to have pregnancy-related SE. Patients with eclampsia were not included as they were usually cared for in our obstetric unit.ResultsSeven patients with pregnancy-related SE were identified (2.1% of all cases of SE), with the majority (85%) occurring de novo except for one patient who had a previous history of epilepsy-related SE due to withdrawal of antiepileptic medication. In terms of etiology, limbic encephalitis and cerebral venous sinus thrombosis were the two main etiologies of de novo SE associated with pregnancy. The overall mortality rate was 28.5% at discharge, and poor outcomes were especially noted in the patients with limbic encephalitis compared to other etiologies.ConclusionsPregnancy-associated SE is rare and predominantly occurs in patients without a history of epilepsy. An autoimmune etiology should be considered in pregnant patients with de novo SE, which was associated with poor outcomes. Thorough investigations and prompt treatment according to the etiology may be required to improve the final outcomes of both mother and fetus.     

Lacosamide as a new treatment option in status epilepticus

Status epilepticus is among the most common neurologic emergencies, with a mortality rate of up to 20%. The most important therapeutic goal is fast, effective, and well‐tolerated cessation of status epilepticus. Intravenous phenytoin/fosphenytoin, phenobarbital, or valproate is the current standard treatment after failure of benzodiazepines. Lacosamide as a new antiepileptic drug has been available as an intravenous solution since 2009. To date, PubMed lists 19 studies (10 single case reports and 9 case series), reporting a total of 136 episodes of refractory status epilepticus (50% nonconvulsive status epilepticus, 31% focal status epilepticus, and 19% convulsive status epilepticus) treated with lacosamide. The most often used bolus dose was 200–400 mg over 3–5 min. The overall success rate was 56% (76/136). Adverse events (AEs) were reported in 25% (34/136) of patients: mild sedation in 25 cases, 1 patient with possible angioedema, 2 with allergic skin reaction, 4 with hypotension, and 1 with pruritus. One patient developed a third‐degree atrioventricular (AV) block and paroxysmal asystole. Overall, the rate of AEs was low. Current evidence on the use of intravenous lacosamide in acute seizures and status epilepticus is restricted to retrospective case reports and case series (class IV). Further prospective studies to inform clinicians are necessary.